Apoptosis is a form of physiological cell death that is thought to be an important mechanism for the elimination of abnormal or transformed cells. It is also the form of death induced in cancer cells by chemotherapeutic drugs and gamma-irradiation. An agent which interferes with the process of apoptosis could potentially promote tumor formation as well as interfere with cancer therapies. Our previous studies demonstrated that nicotine inhibits cytokine and chemotherapeutic drug- induced apoptosis of a ability of nicotine to inhibit apoptosis may promote tobacco-related carcinogenesis as well as decrease the efficacy of cancer therapies. Our previous studies demonstrated that nicotine inhibits cytokine and chemotherapeutic drug-induced apoptosis of a variety of tumor cell lines, including those types related to tobacco use. We hypothesize that the ability of nicotine to inhibit to inhibit apoptosis may promote tobacco-related carcinogenesis as well as decrease the efficacy of cancer therapies. The aims of this proposal are: 1) to further define the conditions under which nicotine inhibits apoptosis in tumor cell lines and in normal epithelial cells; 2) investigate the molecular mechanism in which nicotine obstructs the apoptotic pathway; 3) determine if nicotine will decrease the efficacy of chemotherapy in a mouse model. We will examine the effects of acuter high dose, chronic low dose exposure, and the reversibility of nicotine's ability to inhibit apoptosis in tumor cell lines and normal lung epithelial cells. We will test the effects of nicotine on different inducers of apoptosis in tumor cell lines and normal lung epithelial cells. We will test the effects of nicotine on different inducers of apoptosis including ionizing radiation, chemotherapeutic drugs, and anoikis (enforced cell detachment). We will analyze the mechanism of inhibition with special focus on signal transduction pathways that have been implicated as negative modulators of apoptosis. Studies will analyze the effects of nicotine on expression of Bcl-2, protein kinase C activity, the mitogen activated protein kinase pathway, and the PI3-kinase/Akt kinase pathway. Mice bearing transplantable tumors will be treated with different chemotherapeutic drugs with and without co-administration of nicotine to determine if there is a reduction in the therapeutic effect. The results of these studies should increase our understanding of the mechanisms underlying development of cancer in cigarette smokers and in smokeless tobacco users. This investigation will also provide insight into the potential hazards of continued tobacco use in patients undergoing cancer therapy.